The present invention describes novel nitrosated and/or nitrosylated potassium channel activators, and novel compositions comprising at least one nitrosated and/or nitrosylated potassium channel activator, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The present invention also provides novel compositions comprising at least one potassium channel activator, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing cardiovascular disorders, cerebrovascular disorders, hypertension, asthma, baldness, urinary incontinence, epilepsy, sleep disorders, gastrointestinal disorders, migraines, irritable bowel syndrome, and sensitive skin.
Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the International Journal of Gynecology and Obstetrics, 51(3):265-277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the xe2x80x9corgasmic platform,xe2x80x9d an area at the distal third of the vagina where blood becomes sequestered. Localized perivaginal swelling and vaginal lubrication make up the changes in this stage of sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of the uterus occurs. In the male, vasodilation of the cavernosal arteries and closure of the venous channels that drain the penis produce an erection. The third stage of sexual response is orgasm, while the fourth stage is resolution. Interruption or absence of any of the stages of the sexual response cycle can result in sexual dysfunction. One study found that 35% of males and 42% of females reported some form of sexual dysfunction. Read et al, J. Public Health Med., 19(4):387-391 (1997).
While there are obvious differences in the sexual response between males and females, one common aspect of the sexual response is the erectile response. The erectile response in both males and females is the result of engorgement of the erectile tissues of the genitalia with blood which is caused by the relaxation of smooth muscles in the arteries serving the genitalia.
In males, some pharmacological methods of treating sexual dysfunctions are available, however, such methods have not proven to be highly satisfactory or without potentially severe side-effects. Papaverine is now widely used to treat impotence. Papaverine is generally effective in cases where the dysfunction is psychogenic or neurogenic and where severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific antagonist and hypotensive, into corpus cavernosum has been found to cause an erection sufficient for vaginal penetration, however, these treatments are not without the serious and often painful side effect of priapism. Also, in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an xcex1-adrenergic antagonist, is used. As an alternative or, in some cases, as an adjunct to xcex1-adrenergic blockade, prostaglandin E1 (PGE1) has been administered via intracavernosal injection. A major side effect frequently associated with intracorprally delivered PGE1 is penile pain and burning.
Potassium channel activators have been developed to treat numerous diseases. For example, Gopalakrishnan et al, Drug Dev. Res. 28:95-127 (1993) describe this class of compounds for treating diseases such as hypertension, asthma, hair growth, ischemia and urinary incontinence; U.S. Pat. Nos. 5,256,688 and 5,354,764 disclose the use of pinacidil or cromakalim for treating myocardial ischemia; U.S. Pat. No. 5,262,419 discloses treating ulcerative gastrointestinal conditions; U.S. Pat. No. 4,792,564 discloses treating and preventing cerebral vasospasms; U.S. Pat. No. 4,789,679 discloses treating incontinence; U.S. Pat. No. 4,057,636 discloses the use of potassium channel activators for lowering blood pressure; U.S. Pat. No. 5,869,509 discloses the use of potassium channel activators for treating ischemia, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, male erectile dysfunction and urinary incontinence; WO 99/11238 discloses the use of potassium channel activators for treating sensitive skin, particularly for the elimination of itching, pruritus, stabbing pains, tingling and/or erythema; Aizawa et al, J. Cardiovasc. Pharmcol. 10:S123-S129 (1987) describes the use of nicorandil for treating ischemic heart disease; U.S. Pat. No. 4,617,311 discloses the use of potassium channel activators for treating asthma; and Boselli et al, Clin. Neuropharmacol 20(3):252-263 (1997) compares the use of lorazepam with other compounds as sedatives for treating insomnia. The disclosure of each of these patents, applications and publications is incorporated by reference herein in their entirety.
There is a need in the art for new and improved treatments of male and female sexual dysfunctions and other diseases, particularly treatments that do not have the undesirable side effects of those agents currently used. The present invention is directed to these, as well as other, important ends.
Nitric oxide (NO) has been shown to mediate a number of actions, including the bactericidal and tumoricidal actions of macrophages and blood vessel relaxation of endothelial cells. NO and NO donors have also been implicated as mediators of nonvascular smooth muscle relaxation. As described herein, this effect includes the dilation of the corpus cavernous smooth muscle, an event involved in the sexual response process in both males and females. However, the effects of modified potassium channel activators, which are directly or indirectly linked with a nitric oxide adduct, and which are optionally used in conjunction with NO donors, have not been previously investigated.
In arriving at the present invention, it was unexpectedly discovered that the adverse effects associated with potassium channel activators can be avoided by the use of nitrosated and/or nitrosylated potassium channel activators or by the use of at least one potassium channel activator in combination with at least one nitric oxide donor. Such adverse effects include postural hypotension, headaches, dizziness, palpitations, gastric pain, nausea and vomiting. The smooth muscle relaxant properties of the potassium channel activators and of compounds that donate, release or transfer nitrogen monoxide or elevate levels of endogenous nitric oxide or endothelium-derived relaxing factor (EDRF) or are substrates for nitric oxide synthase work together to permit the same efficacy with lower doses of the potassium channel activators or work synergistically to produce an effect that is greater than the additive effects of the potassium channel activators and the compounds that donate, release or transfer nitrogen monoxide or elevate levels of endogenous nitric oxide or EDRF or is a substrates for nitric oxide synthase.
One aspect of the present invention provides novel nitrosated and/or nitrosylated potassium channel activators. The potassium channel activators can be nitrosated and/or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and/or nitrogen. The present invention also provides compositions comprising a therapeutically effective amount of such compounds in a pharmaceutically acceptable carrier.
Another aspect of the present invention provides compositions comprising a therapeutically effective amount of at least one potassium channel activator, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x80x94), or as the neutral species, nitric oxide (NO.), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The present invention also provides for such compositions in a pharmaceutically acceptable carrier.
Yet another aspect of the present invention provides compositions comprising a therapeutically effective amount of at least one potassium channel activator, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), at least one vasoactive drug, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x80x94), or as the neutral species, nitric oxide (NO.), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Yet another aspect of the present invention provides methods for treating and/or preventing sexual dysfunctions and/or enhancing sexual responses in patients, including males and females, by administering to a patient in need thereof a therapeutically effective amount of at least one nitrosated and/or nitrosylated potassium channel activator and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x80x94), or as the neutral species, nitric oxide (NO.), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The methods can further comprise administering a therapeutically effective amount of at least one vasoactive agent. Alternatively, the methods for treating and/or preventing sexual dysfunctions and/or enhancing sexual responses in patients, including males and females, can comprise administering a therapeutically effective amount of at least one nitrosated and/or nitrosylated potassium channel activator, at least one vasoactive agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x80x94), or as the neutral species, nitric oxide (NO.), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated potassium channel activators, nitric oxide donors, and/or vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
The present invention also provides methods for treating and/or preventing sexual dysfunctions and/or enhancing sexual responses in patients, including males and females, by administering to a patient in need thereof a therapeutically effective amount of at least one potassium channel activator and at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x80x94), or as the neutral species, nitric oxide (NO.), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The methods can further comprise administering a therapeutically effective amount of at least one vasoactive agent. Alternatively, the methods for treating and/or preventing sexual dysfunctions and/or enhancing sexual responses in patients, including males and females, can comprise administering a therapeutically effective amount of at least one potassium channel activator, at least one vasoactive agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x80x94), or as the neutral species, nitric oxide (NO.), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The potassium channel activators, the nitric oxide donors, and the vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
The present invention also provides methods using the compounds and compositions described herein to prevent or treat cardiovascular disorders, such as congestive heart failure and myocardial ischemia, especially angina pectoris and arrhythmia; cerebrovascular disorders, including those associated with cerebral ischemia; hypertension; asthma; baldness; urinary incontinence; epilepsy; sleep disorders; gastrointestinal disorders; migraines; irritable bowel syndrome and sensitive skin, by administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds and/or compositions described herein. In these methods, the potassium channel activators that are optionally nitrosated and/or nitrosylated, nitric oxide donors and vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
These and other aspects of the present invention are described in detail herein.